Project Summary and Abstract High density lipoproteins (HDL) have a well-established inverse correlation with the occurrence of cardiovascular disease. However, the functional activities of HDL which mediate this protection are not well understood. HDL are micellar complexes composed of lipids and an array of different proteins which are likely to confer specific functions to the HDL particles that carry them. Of more than 85 identified HDL associated proteins, over 20% have known functions related to protease inhibition, the majority of these are members of the Serine Protease Inhibitor (SERPIN) family of proteins. This proposal will examine the structural interaction between the most abundant HDL-bound SERPIN, alpha-1-antitrypsin (A1AT), and HDL particles and also the functional consequences of this interaction. Dr. Gordon will use individual particle electron tomography, a novel molecular imaging technique, to determine the structural details of the interaction between A1AT and HDL and to identify the region of the A1AT protein involved in binding. Using reconstituted HDL, enriched with A1AT, Dr. Gordon will investigate the capacity of these particles to reduce vascular protease activity and subsequent atherosclerosis development in a mouse model. Additionally, a novel HDL targeting small peptide mimetic of A1AT will be developed and evaluated for its capacity to prevent atherosclerosis development and to stabilize existing plaque in an effort to prevent thrombus formation and subsequent cardiovascular events such as heart attack, stroke, or pulmonary embolism. This work has been proposed by Dr. Scott Gordon, a postdoctoral fellow of the National Heart, Lung, and Blood Institute at the National Institutes of Health, as part of an NHLBI K22 Career Transition Award. Dr. Gordon performed his graduate studies on the composition and function of HDL and has extended his previous work in the current proposal. A team of experienced mentors with a variety of skills related to aspects of this proposal has been assembled by Dr. Gordon to assist in the successful completion of the proposed research as well as the successful transition of Dr. Gordon into an independent tenure track academic faculty position at a major research university in the United States.